Spiro-indolines as Y5 receptor antagonists

ABSTRACT

Compounds of general structural formula I such as that shown in structural formula II  
                 
 
     are selective NPY Y 5  receptor antagonists, useful in the treatment of obesity and the complications associated therewith.

SUMMARY OF THE INVENTION

[0001] This invention is concerned with compounds which arespiro-indolines of general structure:

[0002] The invention is also concerned with the use of these novelcompounds to selectively antagonize the Y5 receptors and thereby inhibitobsessive food intake and the resulting obesity and complicationsassociated therewith.

[0003] The invention is also concerned with pharmaceutical formulationscomprising one of the compounds as active ingredient.

[0004] The invention is further concerned with processes for preparingthe compounds of this invention.

BACKGROUND OF THE INVENTION

[0005] Neuropeptide Y (NPY) is a member of the pancreatic polypeptidefamily with widespread distribution throughout the mammalian nervoussystem. NPY and its relatives elicit a broad range of physiologicaleffects through activation of at least six G protein-coupled receptorsubtypes known as Y1, Y2, Y3, Y4, Y5 and Y6. The Y5 subtype wasisolated, characterized and reported recently in U.S. Pat. No. 5,602,024(WO 96/16542).

[0006] The cited WO 96/16542 also reports the discovery of chemicalcompounds which bind selectively to the Y5 receptor and which act asantagonists of the Y5 receptor, several of which were shown to inhibitfood intake in rats.

[0007] Now with the present invention there is provided a class ofcompounds characterized as spiro-indolines, which are useful in thetreatment, control or prevention of diseases, disorders or conditionsmediated by activation of the Y5 receptor. These compounds are, thus,useful in the treatment of obesity in man or animals and in conditionscaused by or exacerbated by obesity.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The compounds of this invention are represented by the compoundof structural formula I:

[0009] or a pharmaceutically acceptable salt thereof, wherein;

[0010] V, W, X and Z are independently selected from CH and N;

[0011] R¹ is H, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, or Cl;

[0012] R² is S(O)_(n)R⁶, COR⁶ or CHO, wherein

[0013] n is 0, 1 or2; and

[0014] R⁶ is N(R³)₂ or C₁₋₃ alkyl;

[0015] R³ is independently H or C₁₋₃ alkyl;

[0016] Ar is aryl or heteroaryl;

[0017] R⁴ and R⁵ are independently selected from:

[0018] (1) hydrogen,

[0019] (2) aryl, either unsubstituted or substituted with

[0020] (a) halo

[0021] (b) C₁₋₃ alkoxy,

[0022] (c) —N(C₁₋₃ alkyl)₂,

[0023] (d) C₂₋₄ alkanoyl, or

[0024] (e) aryl,

[0025] (3) nitro,

[0026] (4) C₁₋₅ alkyl,

[0027] (5) C₁₋₅ alkoxy,

[0028] (6) hydroxy-C₁₋₃ alkyl,

[0029] (7) carboxy,

[0030] (8) halo,

[0031] (9) C₁₋₅ alkylthio,

[0032] (10) C₁₋₅ alkoxycarbonyl,

[0033] (11) pyridylcarbonyl,

[0034] (12) benzoyl,

[0035] (13) phenyl-C₁₋₃ alkoxy,

[0036] (14) pyridyl, either unsubstituted or substituted with C₁₋₃ alkylor C₁₋₃ alkoxy,

[0037] (15) C₃₋₆ cycloalkyl,

[0038] (16) oxazolyl,

[0039] (17) thiazolyl,

[0040] (18) triazolyl,

[0041] (19) phenoxy or

[0042] (20) C₂₋₆ alkanoyl.

[0043] The term “alkyl” means linear and branched structures andcombinations thereof, containing the indicated number of carbon atoms.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, s- and t-butyl, pentyl, hexyl and the like.

[0044] “Cycloalkyl” means a hydrocarbon having the indicated number ofcarbon atoms, containing one or more rings. Examples of cycloalkylgroups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike.

[0045] “Halogen” or “halo” includes F, Cl, Br, and I unless otherwisespecified.

[0046] “Heteroaryl” is a 5- or 6-membered aromatic heterocycle, or abenzo- or pyrido-fused version thereof, all having, besides carbonatoms, 1 to 3 hetero atoms selected from N, O, and S as atom(s)constituting the ring. Examples thereof include thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyridyl, benzothienyl, benzofuranyl, indolyl, pyrimidinyl,pyrazinyl, pyridazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl,benzopyrazolyl, benzimidazolyl, pyridothiazolyl, quinolyl, isoquinolylor triazolyl.

[0047] “Aryl” is phenyl or naphthyl.

[0048] “Alkoxy” means linear and branched structures and combinationsthereof, containing the indictaed number of carbon atoms. Examples ofalkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-and t-butoxy, pentoxy, and the like.

[0049] “Alkanoyl” means linear and branched structures and combinationsthereof, containing the indicated number of carbon atoms. Examples ofalkanoyl groups include, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl and the like.

[0050] One embodiment of the novel compounds of this invention is thatwherein Ar is phenyl of structural formula I(a)

[0051] or a pharmaceutically acceptable salt thereof.

[0052] A class of compounds within this embodiment is that wherein X andZ are both nitrogen, and V and W are both —CH═.

[0053] A sub-class is that wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂NH₂.

[0054] A sub-sub-class of the compounds of this embodiment is thatwherein R⁴ and R⁵ are independently selected from: phenyl, pyridyl,benzoyl, halophenyl, phenoxy, C₁₋₅ alkylpyridyl, benzhydryl, phenyl-C₁₋₃alkoxy, NO₂, C₂₋₄ alkanoyl, halo, C₁₋₅ alkoxy, C₁₋₃ alkoxycarbonyl, C₁₋₅alkylthio, triazolyl, carboxy, hydrogen, C₁₋₅ alkyl, pyridylcarbonyl,and C₁₋₃ alkoxyphenyl.

[0055] Typical of the compounds of this sub-sub-class are those whereinR² and phenyl(R⁴)(R⁵) are as shown in the following TABLE I: TABLE I

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂NH₂

—SO₂C₂H₅

—SO₂CH(CH₃)₂

—SO₂CH(CH₃)₂

[0056] A second embodiment of the compounds of this invention is thatwherein Ar is a 5- or 6-membered heteroaryl having, besides carbonatoms, 1 to 3 hetero atoms selected from N, O and S as atomsconstituting the ring, or benzo- or pyrido-fused versions thereof, ofstructural formula I(b);

[0057] or a pharmaceutically acceptable salt thereof.

[0058] A class of compounds within this embodiment, is that wherein Xand Z are both nitrogen, and V and W are both —CH═.

[0059] A sub-class is that wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂N(C₁₋₃alkyl)₂.

[0060] A sub-sub-class of compounds within this embodiment is thatwherein the heteroaryl group, Ar, is selected from: thiazolyl,thiadiazolyl, pyrazolyl, pyridyl, benzothiazolyl, oxazolyl,pyridothiazolyl, benzoxazolyl, quinolyl, pyrazinyl, thienyl, isoxazolyl,pyrimidinyl, benzimidazolyl, oxadiazolyl and imidazolyl.

[0061] Typical of the compounds of this sub-sub-class are those whereinR² and Ar(R⁴)(R⁵) are as shown in TABLE II. TABLE II

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂NH₂

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂N(CH₃)₂

—SO₂NH₂

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅

—SO₂CH₃

—SO₂CH₃

—SO₂C₂H₅

—SO₂C₂H₅

[0062] A third embodiment of the compounds of this invention is thatwherein one of X and Z is N and the other is —CH═ of structural formula1(c):

[0063] or a pharmaceutically acceptable salt thereof.

[0064] A class of compounds within this embodiment is that wherein X isN, Z is —CH═ and V and W are both —CH═

[0065] Typical of the compounds within this class are those shown inTABLE III: TABLE III

R²

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

[0066] A second class of compounds within this embodiment is thatwherein X is —CH═, Z is N and V and W are both —CH═.

[0067] Typical of the compounds within this second class are those shownin TABLE IV: TABLE IV

R² X

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

—SO₂CH₃

[0068] A fourth embodiment of the compounds of this invention is thatwherein R² is —COR⁶ of structural formula I(d):

[0069] or a pharmaceutically acceptable salt thereof.

[0070] A class of compounds within this embodiment is that wherein X andZ are both N and V and W are both —CH═.

[0071] Typical of the compounds within this embodiment are those shownin TABLE V: TABLE V

R⁶

—CH₃

—CH₃

—CH₃

[0072] A fifth embodiment of the compounds of this invention is thatwherein one of V or W is nitrogen (N) and the other is —CH═ of formulaI(e):

[0073] A class of compounds within this embodiment is that wherein R¹and R³ are H and X and Z are both nitrogen.

[0074] A sub-class of compounds within this class is that wherein R² is—SO₂CH₃.

[0075] Typical of the compounds within this sub-class are those depictedin the following TABLE VI: TABLE VI

V W

—N═ —CH═

—CH═ —N═

—CH═ —N═

—CH═ —N═

[0076] Some of the compounds described herein contain one or moreasymmetric centers and may thus give rise to diastereomers and opticalisomers. The present invention is meant to include such possiblediastereomers as well as their racemic and resolved, enantiomericallypure forms and pharmaceutically acceptable salts thereof.

[0077] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic acids or basesincluding inorganic and organic acids and bases.

[0078] When the compound of the present invention is acidic, salts maybe prepared from inorganic bases such as aluminum, ammonium, calcium,copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc,and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine,glucosamine, histidine, hydrabamine, N-(2-hydroxyethyl)piperidine,N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

[0079] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, adipic,aspartic, 1,5-naphthalenedisulfonic, benzenesulfonic, benzoic,camphorsulfonic, citric, 1,2-ethanedisulfonic, ethanesulfonic,ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic,hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic,succinic, sulfuric, tartaric, p-toluenesulfonic acid, undecanoic,10-undecenoic, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuricand tartaric acids. It will be understood that in the materials whichfollows, references to the compounds of Formula I are meant to alsoinclude the pharmaceutically acceptable salts.

[0080] Another aspect of this invention are the processes used toprepare the novel compounds.

[0081] Compounds in which X and Z are both nitrogen are prepared by thegeneral procedures outlined in Scheme I.

[0082] The Cbz spiroindoline 3 is prepared according to the methoddescribed in Tetrahedron 53, 10983-10992 (1997).. In one procedure 3 istreated with a reagent R²Cl, wherein R² is as defined above, in thepresence of a base such as a tertiary amine, including triethylamine(Et₃N), diisopropylethylamine (DIEA), or pyridine, followed by removalof the carbobenzyloxy (Cbz) protecting group by hydrogenolysis withhydrogen over a noble metal catalyst at room temperature and pressure ina lower alcohol such as methanol or ethanol, or an etherial solvent suchas diethyl ether of tetrahydrofuran (THF) or mixtures thereof to give 4following the methods described in Tetrahedron 53 10983-10992, (1997)wherein the preparation of 4 is described wherein R² is —SO₂CH₃.

[0083] Compound 4 (with R² protected if necessary) is then treated witha phenyl carbamate of structure PHOCONH—Ar(R⁴)(R⁵) in the presence of atertiary amine in an organic solvent such as a haloalkane such aschloroform, methylene chloride, ethylene dichloride or the like atreflux temperature or in the presence of NaOH in H₂O/DMSO, until thereaction is complete, usually in about ½ to about 3 hours followed bydeprotection of the R² group if necessary, to provide the CompoundI(R³═H).

[0084] In the above procedures, the phenyl carbamates are prepared byreaction of the corresponding amines of structure NH₂—Ar(R⁴)(R⁵) whichare commercially available or readily synthesized, with phenylchloroformate in pyridine at room temperature as described in Example Ibelow.

[0085] Alternatively, Compound I is prepared by treatment of 4 with anisocyanate of structure OCN—Ar(R⁴)(R⁵) in a chlorinated alkane at refluxtemperature until the reaction is complete in about 4 to about 12 hours.

[0086] Compound I can also be prepared by conducting the aboveprocedures in the reverse order. The indoline nitrogen of 3 is protectedwith Boc by treatment with di-tert-butyl dicarbonate in the presence ofa base, such as, NaOH or triethyl amine, in an inert solvent such asaqueous dioxane or methanol and the Cbz group is hydrogenolyzed withhydrogen and a noble metal catalyst to give 5. Treatment of 5 witheither the phenyl carbamate or isocyanate described earlier provides 6which upon deprotecting with a strong acid such as hydrochloric ortrifluoroacetic acid in an inert solvent such as ethyl acetate ormethylene chloride and treatment with R²Cl in the presence of a tertiaryamine as described above provides Compound I( R³═H).

[0087] Compounds of this invention are antagonists of the Y5 receptorand as such are useful for the prevention and treatment of disorders ordiseases associated with the Y5 receptor sub-type, preferably for thetreatment of feeding disorders such as obesity, anorexia nervosa andbullimia nervosa, and other abnormal conditions, such as diabetes,hypertension, hyperlipemia, hypercholesterolemia, congestive heartfailure, renal dysfunction, sexual/reproductive disorders, depression,anxiety, shock, epileptic seizure, memory loss, sleep disturbance, pain,migraine, cerebral hemorrhage, nasal congestion, gastrointestinaldisorders, arthritis and immunodeficiency syndrome.

[0088] The Y5 antagonists of this invention may also be used incombination with other anti-obesity agents for increased efficacy in theprevention and treatment of obesity Such agents would include, but notbe limited to: sibutramine; dexenfluramine; leptin; growth hormonesecretagogues such as those disclosed and specifically described in U.S.Pat. No. 5,536,716; melanocortin agonists such as Melanotan II; Beta-3agonists such as those disclosed and specifically described in patentpublications WO94/18161, WO95/29159, WO97/46556, WO98/04526 andWO98/32753; 5HT-2 agonists; orexin antagonists; melanin concentratinghormone antagonists; galanin antagonists; CCK agonists; GLP-1 agonists;corticotropin-releasing hormone agonists; and Y1 antagonists.

[0089] The method of treatment of this invention comprises a method ofantagonizing the Y5 receptor and treating Y5 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the Y5 receptor in preference to the other NPYreceptors.

[0090] Dosage levels of the order of from about 0.01 mg to about 140mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, obesity may be effectively preventedor treated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day.

[0091] For the treatment of any of these Y5 receptor mediated diseases,compounds of the invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

[0092] The novel pharmaceutical compositions of this inventioncontaining the active ingredient may be in a form suitable for oral use,for example, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules, orsyrups or elixirs. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tabletsfor controlled release.

[0093] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients is mixed withwater or miscible solvents such as propylene glycol, PEGs and ethanol,or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0094] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

[0095] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0096] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

[0097] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

[0098] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. Cosolvents such as ethanol, propylene glycol or polyethyleneglycols may also be used. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0099] Compounds of the invention may also be administered in the formof a suppository for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenonirritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0100] For topical use, creams, ointments, gels, solutions orsuspensions, etc., containing the compound of Formula I are employed.(For purposes of this application, topical application shall includemouth washes and gargles.) Topical formulations may generally becomprised of a pharmaceutical carrier, cosolvent, emulsifier,penetration enhancer, preservative system, and emollient.

[0101] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay contain from 0.5 mg to 5 g of active agent compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofan active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0102] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe age, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

[0103] The following Examples describe the laboratory synthesis ofspecific compounds of the invention and are not meant to limit the scopeof the invention in any way with respect to compounds or processes. Itis understood that, although specific reagents, solvents, temperaturesand time periods are used, there are many possible equivalentalternatives that can be used to produce similar results. This inventionis meant to include such equivalents.

[0104] Abbreviations used herein have the following meanings:ABBREVIATION DEFINITION Ac acetyl Boc t-butoxycarbony BSA bovine serumalbumin MCPBA m-chloroperbenzoic acid Cbz carbobenzyloxy Et ethyl HEPES[4-(2-hydroxyethyl)-1- piperazineethane sulfonic acid] IPE isopropylether Me methyl PCC pyridium chlorochromate PhMe—MeCN tolueneacetonitrile PMSF -toluene sulfonylfluoride WSC.HCl water solublecarboiimide.HCl

EXAMPLE 1 1-Methanesulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide100

[0105]

[0106] Step 1: Preparation of Compound 1-2

[0107] Phenyl chloroformate (0.64 mL, 5.1 mmol) was added to avigorously stirred solution of 2-amino-5-phenylpyrazine 1-1 (794 mg,4.64 mmol) in pyridine (10 mL) at room temperature. After being stirredat room temperature overnight, the mixture was diluted with EtOAc togive a suspension, in which the desired compound precipitated out. Thesuspension was successively washed with 1 N KHSO₄, brine and dist.water. The precipitate was collected by filtration and dried to givephenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (847 mg, 63%). The filtratewas concentrated under reduced pressure to produce precipitate, whichwas collected and dried to give the second crop (340 mg, 25%).

[0108] Step 2: Preparation of Compound 100

[0109] A mixture of phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (7, 350mg, 1.20 mmol),1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 1-3 (400mg, 1.32 mmol) and Et3N (0.5 mL, 3.6 mmol) in CHCl3 (6 mL) was heated toreflux for 3 h. After cooling, the mixture was diluted with EtOAc,washed with 10% citric acid, sat. NaHCO₃ and brine, dried over MgSO₄,and concentrated under reduced pressure to start precipitation. Theprecipitate was collected by filtration and dried in vacuo to give 100(517 mg, 93%) as a white powder.

[0110] m.p.: 201-203° C.

[0111]¹H-NMR (DMSO-d6) was consistent with the proposed title structure.FABMS: 464 (M+H)

[0112] Compounds #101-#137 were prepared from1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride and theappropriate phenyl carbamates according to the procedure described inExample 1.

[0113] #101

[0114]N-[5-(3-fluorophenyl)-2-pyrazinyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0115] m.p.: 203-205° C.

[0116] #102

[0117]N-[5-(2-methoxyphenyl)-2-pyrazinyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0118] m.p.: 186-188° C.

[0119] #103

[0120] N-[5 -(2-chlorophenyl)-2-pyrazinyl]- 1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0121] m.p.: 197-199° C.

[0122] #104

[0123]1-methylsulfonyl-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0124] m.p.: 234-235° C.

[0125] #105

[0126]1-methylsulfonyl-N-[5-(2-propenyl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0127] m.p.: 180.5-182.7° C.

[0128] #106

[0129]1-methylsulfonyl-N-[4-(1-mehtyl-2-imidazolyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

[0130] m.p.: 196-198° C.

[0131] #107

[0132]N-[4-(2-ethyl-4-thiazolyl)phenyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0133] m.p.: 242-242.5° C.

[0134] #108

[0135]1-methylsulfonyl-N-[4-(4-pyridyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0136] m.p.: 272-274° C.

[0137] #109

[0138]N-[4-(2-ethyl-4-pyridyl)phenyl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

[0139] m.p.: 220-222° C.

[0140] #110

[0141]N-(4-benzoylphenyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

[0142] m.p.: 222-225° C.

[0143] #111

[0144]1-methylsulfonyl-N-[4-(2-thiazolyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0145] m.p.: 143.2-147.4° C.

[0146] #112

[0147]1-methylsulfonyl-N-(5-phenyl-2-pyridyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0148] m.p.: 214° C.

[0149] #113

[0150]1-methylsulfonyl-N-(2-phenyl-5-pyrimidinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0151] m.p.: 251-253° C.

[0152] #114

[0153]1-methylsulfonyl-N-(2-phenyl-5-pyridyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0154] m.p.: 224° C.

[0155] #115

[0156]1-methylsulfonyl-N-(5-phenyl-2-pyrimidinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0157] m.p.: 122-123° C.

[0158] #116

[0159]1-methylsulfonyl-N-[2-(1-pyrrolidinyl)-5-pyridyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0160] m.p.: 252-254° C.

[0161] #117

[0162]N-[5-(4-chlorophenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0163] m.p.: 152-156° C.

[0164] #118

[0165]N-[5-(5-methoxy-3-pyridyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0166] m.p.: 213-215° C.

[0167] #119

[0168]1-methylsulfonyl-N-(4-phenyloxazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0169] m.p.: 189-192° C.

[0170] #120

[0171]N-[5-(3-methoxyphenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0172] m.p.: 158-160° C.

[0173] #121

[0174]1-methylsulfonyl-N-(3-phenylisoxazol-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0175] m.p.: 235-237° C.

[0176] #122

[0177]N-[5-(3-chlorophenyl)pyrrazol-3-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0178] m.p.: 185-187° C.

[0179] #123

[0180]1-methylsulfonyl-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0181] m.p.: 133-136° C.

[0182] #124

[0183]N-[4-(3-methoxyphenyl)oxazol-2-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidecolorless amorphous solid.

[0184] 1H-NMR (DMSO-d6) ppm: 1.62-1.87 (4H, m), 2.96-3.09 (2 H, m), 3.05(3H, s), 3.78 (3H, s), 3.92 (2H, s), 4.04-4.16 (2H, m), 6.87 (1H, m),7.04 (1H, m), 7.19-7.37 (7H, m), 8.35 (1H, br s).

[0185] #125

[0186]1-methylsulfonyl-N-(5-phenylpyrrazol-3-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0187] m.p.: 163° C.

[0188] #126

[0189]N-[1-(3-methoxyphenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0190] m.p.: 216-218° C.

[0191] #127

[0192]N-[1-(3-chlorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0193] m.p.: 232-234° C.

[0194] #128

[0195]N-(4-methoxybenzoxazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0196] m.p.: 195-199° C.

[0197] #129

[0198]N-(5-fluorobenzothiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0199] m.p.: 243-244° C.

[0200] #130

[0201]1-methylsulfonyl-N-(6-methylquinoxalin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0202] m.p.: 224-225° C.

[0203] #131

[0204]1-methylsulfonyl-N-(8-methylquinolin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0205] m.p.: 219-220° C.

[0206] #132

[0207]N-(7-chloroquinoxalin-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0208] m.p.: 213-214° C.

[0209] #133

[0210]N-(6-methoxypyrido[2,2-d]thiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0211] m.p.: 179-182° C.

[0212] #134

[0213]N-(5-methoxybenzoxazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0214] m.p.: 194-196° C.

[0215] #135

[0216]N-(5-chlorobenzoazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0217] m.p.: 172-176° C.

[0218] #136

[0219]1-methylsulfonyl-N-(1,5-naphthyridin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

[0220] 1H-NMR (DMSO-d6) ppm: 1.64-1.92 (4H, m), 2.95-3.16 (2H, m), 3.05(3H, s), 3.93 (2H, s), 4.18-4.30 (2H, m), 7.04 (1H, m), 7.18-7.37 (3H,m), 7.66 (1H, dd, J=4.3, 8.5 Hz), 8.14 (1H, m), 8.22-8.30 (2H, m), 8.80(1H, m), 9.84 (1H, br s).

[0221] #137

[0222]N-(4-methylbenzothiazol-2-yl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0223] m.p.: 182-183° C.

[0224] Compound #138 was prepared from7-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 1.

[0225] #138

[0226]7-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

[0227] 1H-NMR (CDCl3) δ ppm: 1.62-1.96 (4H, m), 3.09-3.18 (2H, m), 3.33(3H, s), 4.14-4.26 (2H, m), 6.93-7.10 (3H, m), 7.90 (1H, brs), 7.97 (2H,d, J=6.8 Hz), 8.56 (1H, s), 9.54 (1H, d, J=2.3 Hz).

[0228] Compound #139 was prepared from6-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 1.

[0229] #139

[0230]6-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0231] m.p.: 234-237° C.

[0232] Compounds #140-#144 were prepared from1-ethylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [prepared inanalogy to the method described in U.S. Pat. No. 5,536,716] and thecorresponding phenyl carbamates according to the procedure described inExample 1.

[0233] #140

[0234]1-ethylsulfonyl-N-(1-phenylimidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

[0235] m.p.: 139-140° C.

[0236] #141

[0237]N-(4-benzoylphenyl)-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

[0238] 1H-NMR (CDCl3) δ ppm: 1.44 (3H, t, J=7.4 Hz), 1.80-1.85 (2H, m),1.95-2.04 (2H, m), 3.10-3.20 (2H, m), 3.17 (2H, t, J=7.4 Hz), 3.97 (2H,s), 4.11-4.16 (2H, m), 6.8-6.9 (1H, brs), 7.08 (1H, t, J=7.3 Hz), 7.16(1H, d, J=8.1 Hz), 7.23 (1H, d, J 8.1 Hz), 7.37 (1H, d, J=8.1 Hz),7.48-7.58 (5H, m), 7.76-7.83 (4H, m).

[0239] #142

[0240]N-[5-(4-chlorophenyl)pyrrazol-3-yl]-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0241] m.p.: 249.0-249.8° C.

[0242] #143

[0243]N-[5-(4-chlorophenyl)isoxazol-3-yl]-1-ethylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide

[0244] m.p.: 178.3-178.5° C.

[0245] #144

[0246]1-ethylsulfonyl-N-[1-(3-methoxyphenyl)imidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid

[0247] 1H NMR (CDCl3) δ ppm: 1.43 (3H, t, J=7.5 Hz), 1.75-1.82 (2H, m),1.89-2.00 (2H, m), 3.01-3.13 (2H, m), 3.16 (2H, q, J=7.5 Hz), 3.85 (3H,s), 3.96 (2H, s), 4.10-4.20 (2H, m), 6.86-6.90 (1H, m), 6.93-6.95 (1H,m), 6.98-7.07 (2H, m), 7.14 (1H, d, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz),7.33-7.41 (3H, m), 7.56 (1H, s), 7.60 (1H, s).

[0248] Compound #145 was prepared from1-ethylsulfonyl-5-fluorospiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(1-phenylimidazol-4-yl)carbamate according to the proceduredescribed in Example 1.

[0249] #145

[0250]1-ethylsulfonyl-5-fluoro-N-(1-phenylimidazol-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride

[0251] m.p.: 140-141° C.

[0252] #146

[0253]1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0254] m.p.: 247-249° C.

[0255] #147

[0256]1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0257] m.p.: 234-238° C.

[0258] #148

[0259]6-fluoro-1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0260] m.p.: 242-243° C.

[0261] #149

[0262]6-fluoro-1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0263] m.p.: 237-239° C.

[0264] Compounds #150 and #151 were prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and the corresponding phenyl carbamates according to the proceduredescribed in Example 1.

[0265] #150

[0266]5-fluoro-1-methylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0267] m.p.: 262-266° C.

[0268] #151

[0269]5-fluoro-1-methylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0270] m.p.: 239-240° C.

[0271] #152

[0272]1-ethylsulfonyl-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0273] m.p.: 193-194° C.

[0274] #153

[0275]1-ethylsulfonyl-N-[5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0276] m.p.: 211-214° C.

[0277] Compound #154 was prepared from1-ethylsulfonyl-6-fluorospiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]carbamate accordingto the procedure described in Example 1.

[0278] #154

[0279]1-ethylsulfonyl-6-fluoro-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0280] m.p.: 228-230° C.

[0281] #155

[0282]1-ethylsulfonyl-5-fluoro-N-[5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0283] m.p.: 223-224° C.

EXAMPLE 2N-(2-benzothiazolyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide200

[0284]

[0285] 10 M aqueous NaOH solution (75 uL) was added to a solution of1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 2-1 (225mg, 0.74 mmol) in DMSO (2.5 mL). Phenyl N-(2-benzothiazolyl)carbamate2-2 (200 mg, 0.74 mmol) was added to the mixture, and the resultingmixture was stirred at room temperature for 20 h. The mixtrue wasdiluted with water and extracted with EtOAc. The organic extract waswashed with dil. NaOH and brine, and dried over Na₂SO₄. The solvent wasevaporated, and the residue was purified by silica gel columnchromatography to give 200 (279 mg, 85%) as a colorless amorphous solid.

[0286] 1H-NMR (CDCl3) δ ppm: 1.72-1.84 (2H, m), 1.88-2.00 (2H, m), 2.92(3H, s), 3.06 (2H, t, J=13.0 Hz), 3.86 (2H, s), 4.23-4.33 (2H, m),7.03-7.16 (2H, m), 7.20-7.28 (3H, m), 7.38-7.42 (2H, m), 7.51-7.61 ( H,m), 7.70-7.75 (1H, m). FABMS: 443 (M+H)

[0287] Compound #201 was prepared from1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [preparedby the method described in U.S. Pat. No. 5,536,716] and phenylN-(3-biphenylyl)carbamate according to the procedure described inExample 2.

[0288] #201

[0289] N-3-biphenyl-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamide m.p.: 211-212° C.

[0290] Compound #202 was prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride[prepared in analogy to the method described in U.S. Pat. No. 5,536,716]and phenyl N-(5-phenyl-2-pyrazinyl)carbamate according to the proceduredescribed in Example 2.

[0291] #202

[0292]5-fluoro-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 215.5-215.8° C.

[0293] Compound #203 and #204 were prepared from1-ethylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride [prepared inanalogy to the method described in U.S. Pat. No. 5,536,716] and phenylN-[1-(3-fluorophenyl)-4-imidazolyl]carbamate or phenylN-[1-(2-fluorophenyl)-4-imidazolyl]carbamate, respectively, according tothe procedure described in Example 2.

[0294] #203

[0295]1-ethylsulfonyl-N-[1-(3-fluorophenyl)imidazol-4-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 200-202° C.

[0296] #204

[0297]1-ethylsulfonyl-N-[1-(2-fluorophenyl)imidazol-4-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 180-181.5° C.

EXAMPLE 3N-(4-acetylphenyl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide300

[0298]

[0299] 1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 wasprepared by the procedure described in WO 9602530.

[0300] To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate3-2 (92 mg, 0.36 mmol) in CHCL₃ (3 mL) was added Et₃N (0.23 mL, 1.65mmol) at room temperature. The reaction mixture was heated to reflux for1 h. The resulting suspension was cooled to room temperature. Theresulting suspension was filtered and the filter cake was washed withCHCl₃ to give 300 (47 mg, 33%) as a white solid. m.p.: 233-236° C.

[0301] 1H-NMR (DMSO-d6) was consistent with the proposed titlestructure.FABMS: 429 (M+H)

EXAMPLE 4N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide400

[0302]

[0303] Step 1: Preparation of compound 4-2

[0304] Chlorosulfonyl isocyanate (2.70 mL, 31.1 mmol) was added to astirred solution of tert-butyl alchol (2.96 mL, 31.1 mmol) in EtOAc (400mL) at −40° C., and the resulting mixture was stirred at −20° C. for 20min. The mixture was cooled to −78° C., and a solution of 4-1 (5.00 g,15.5 mmol) in EtOAc (40 mL) was added to the reaction mixture. Themixture was allowed to warm to room temperature and stirred for 14 h.The reaction mixture was washed with sat.NaHCO₃, H₂O and brine, dried(Na₂SO₄), and concentrated. The residual oil was purified by silica gelcolumn chromatography (80 g, hexane-EtOAc 4:13:12:1) to give 4-2 (2.13g, 27%).

[0305] Step 2: Preparation of compound 4-3

[0306] A mixture of compound 4-2 (411 mg, 0.820 mol) and 20% Pd(OH)₂-C(200 mg) in THF (4 mL) and MeOH (4 mL) was stirred under atmosphericpressure of hydrogen for 3 h. The catalyst was filtered off, and thefiltrate was concentrated to give compound 4-3 (215 mg, 71%).

[0307] Step 3: Preparation of compound 4-4

[0308] Et₃N (0.285 mL, 1.46 mmol) was added to a stirred mixture of 4-3(250 mg, 0.681 mmol) and phenyl 5-phenyl-1,3,4-thiadiazol-2-ylcarbamate(202 mg, 0.681 mmol) in CHCl₃ (3 mL), and the mixture was heated toreflux for 3 h. After being cooled to room temperature, the mixture wasconcentrated under reduced pressure. The residual oil was purified bysilica gel column chromatography (10 g, hexane-EtOAc-MeOH 1:1:0→8:8:1)to give 4-4 (208 mg, 54%).

[0309] Step 4 Preparation ofN-(5-phenyl-1,3,4-thiadiazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamide400

[0310] To a stirred mixture of 4-4 in CHCl₃ (1 mL) was added TFA (1 mL).The mixture was stirred for 14 h and concentrated. The resulting mixturewas diluted with EtOAc, washed with sat.NaHCO₃ and brine, dried(Na₂SO₄), and concentrated. The residual solid was crystallized fromEtOAc and isopropyl ether to give compound 400 (130 mg, 76%) ascolorless crystals. m.p.:>300° C.

[0311] 1H-NMR (DMSO-d6) was consistent with the proposed titlestructure. FABMS: 471 (M+H)

[0312] Compounds #401 and #402 were prepared using the appropriatephenyl carbamates in analogy to the procedure of Example 4.

[0313] #401

[0314]N-(4-phenyloxazol-2-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamidecolorless amorphous solid.

[0315] 1H-NMR (DMSO-d6) δ ppm: 1.59-1.69 (2H, m), 1.71-1.85 (2H, m),2.95-3.10 (2H, m), 3.81 (2H, s), 4.05-4.17 (2H, m), 6.98 (1H, m), 7.17(1H, m), 7.18-7.48 (6H, m), 7.68-7.75 (2H, m), 8.33 (1H, s).

[0316] #402

[0317]N-(3-phenylisoxazol-5-yl)-1-sulfamoylspiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 226-227° C.

EXAMPLE 51-Methanesulfamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide500

[0318]

[0319] Step 1: Preparation of compound 5-2

[0320] To a stirred solution of 5-1 (542 mg, 1.08 mmol) and iodomethane(0.202 mL, 3.24 mmol) in DMF (3 mL) was added sodium hydride (contained60% oil dispersion, 52 mg; 1.30 mmol) at 0° C. The mixture was stirredat room temperature for 2 h. The reaction mixture was poured into sat.NH₄Cl and extracted with EtOAc. The organic layer was washed with brine,dried (Na₂SO₄), and concentrated. The residual oil was purified bysilica gel column chromatography (20 g, hexane-EtOAc 6:1→4:1) to givecompound 5-2 (495 mg, 83%).

[0321] Step 2: Preparation of compound 5-3

[0322] A mixture of 450 mg (0.898 mmol) of 5-2 and 200 mg of 20%Pd(OH)₂-C in THF (5 mL) and MeOH (5 mL) was stirred under H₂ for 14 h.The catalyst was then filtered off and the filtrate was concentrated togive compound 5-3 (371 mg, 99%).

[0323] Step 3: Preparation of1-methylsulfamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide500

[0324] To a stirred mixture of 5-3 (185 mg; 0.486 mmol)and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate (144 mg; 0.486 mmol) in CHCl₃ (2mL) was added 0.285 mL (1.46 mmol) of Et₃N. The mixture was refluxed for3 h and cooled to room temperature. Isopropyl ether was added to themixture, and the resulting precipitate was collected by filtration togive crude product of 5-4.

[0325] The crude product was dissolved in CHCl₃ (1 mL), and TFA (1 mL)was added. The mixture was stirred for 14 h and concentrated. Theresidue was dissolved in EtOAc, washed with sat.NaHCO₃ and brine, dried(Na₂SO₄), and concentrated. The residue was triturated with CHCl₃ togive 500 (130 mg, 55%) as a colorless solid. m.p.: 230-231° C.

[0326] 1H-NMR (DMSO-d6) was consistent with the proposed titlestructure. FABMS: 485 (M+H)

EXAMPLE 61-Acetyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide600

[0327]

[0328] Step 1: Preparation of Compound 6-2

[0329] To a solution of 6-1 (267 mg, 0.87 mmol) in THF (5 mL), wereadded Et₃N (0.356 mL, 2.56 mmol) and AcCl (0.092 mL, 1.30 mmol). Theresulting mixture was stirred at room temperature for 1 h. The mixturewas diluted with ethyl acetate, washed with saturated NaHCO₃ and brine,dried (MgSO₄), and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane/ethyl acetate2/1→1/1→1/2→1/4→1/8 (v/v)) to give 6-2 (260 mg, 82%).

[0330] Step 2 Preparation of Compound 6-3

[0331] To a solution of 6-2 (260 mg, 0.71 mmol) in EtOH/THF (6 mL/2 mL),was added 20% Pd(OH)₂-C (110 mg). The resulting mixture was stirredunder H₂ at room temperature overnight. The catalyst was filtered off,and the filtrate was concentrated under reduced pressure to give 6-3(155 mg, 91%).

[0332] Step 3: Preparation of Compound 600

[0333] To a solution of 6-3 (155 mg, 0.67 mmol) in CHCl₃ (3 mL), wereadded Et₃N (0.256 mL, 1.84 mmol) and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate 6-4 (182 mg, 0.61 mmol). Theresulting mixture was stirred under reflux for 1.5 h. After being cooledto room temperature, the reaction mixture was diluted with CHCl₃, washedwith saturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. The residue was triturated withEt₂O to give 600 (176 mg, 66%) as a white solid. m.p.: 260° C.

[0334] 1H-NMR (CDCl3) was consistent with the proposed title structure.FABMS: 434 (M+H).

[0335] Employing the procedure substantially as described in Example 6,but substituting the appropriate phenyl carbamates, for the phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate used in Step 3 thereof, thefollowing compounds were prepared:

[0336] #601

[0337]1-acetyl-N-(4-biphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0338] #602

[0339]1-acetyl-N-(4-phenyloxazol-2-yl)spiro[indoline-3.4′-piperidine]-1′-carboxamide

[0340] #603

[0341]1-acetyl-N-[3-(3-chlorophenyl)isoxazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0342] #604

[0343]1-acetyl-N-[4-(3-pyridyl)phenyl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0344] #605

[0345]1-acetyl-N-[3-(4-chlorophenyl)pyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0346] #606

[0347]1-acetyl-N-(7-methoxybenzothiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0348] #607

[0349]1-acetyl-N-(2-methylbenzothiazol-6-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0350] #608

[0351] 1-acetyl-N-(quinolin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0352] #609

[0353]1-acetyl-N-[3-(3-methoxyphenyl)-1-methylpyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0354] #610

[0355]1-acetyl-N-[3-(3-chlorophenyl)-1-methylpyrazol-5-yl]spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0356] #611

[0357]1-acetyl-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[indoline-3,4′piperidine]-1′-carboxamide

[0358] #612

[0359]1-acetyl-N-(3-phenylpyrazol-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0360] #613

[0361]1-acetyl-N-(2-phenylpyrazin-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0362] #614

[0363] 1-acetyl-N-(3-phenylpyridazin-6-yl)spiro[indoline-3 ,4′-piperidine]-1′-carboxamide

[0364] #615

[0365]1-acetyl-N-(5-phenylpyrimidin-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

[0366] #616

[0367]1-acetyl-N-(2-phenylpyrimidin-5-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

EXAMPLE 71-Formyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide700

[0368]

[0369] Step 1: Preparation of Compound 7-2

[0370] A mixture of 7-1 (300 mg, 3.54 mmol) and p-TsOH.H₂O (10 mg) inethyl formate (5 mL) was stirred under reflux for 20 hr. After beingcooled to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was taken up with CHCl₃, which was washedwith saturated NaHCO₃ and brine. The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane/ethyl acetate 4/1→1/1 (v/v)) to give7-2 (290 mg, 89%).

[0371] Step 2: Preparation of Compound 7-3

[0372] To a solution of 7-2 (290 mg, 0.83 mmol) in EtOH/THF (7 mL/5 mL)was added 20% Pd(OH)₂-C (360 mg). The resulting mixture was stirredunder H₂ at room temperature overnight. The catalyst was filtrated off,and the filtrate was concentrated under reduced pressure to give 7-3(160 mg, 89%).

[0373] Step 3: Preparation of Compound 700

[0374] Compound 7-3 (320 mg, 1.48 mmol) was dissolved in CHCl₃ (5 mL),and Et₃N (0.560 mL, 4.02 mmol) and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate (400 mg, 1.34 mmol) were added.The resulting mixture was stirred under reflux for 1 h. The reactionmixture was cooled to room temperature and diluted with CHCl₃, which waswashed with saturated NaHCO₃ and brine. The organic layer was dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane/ethylacetate/methanol 10/1/0→6/1/0→1/1/0→6/6/1→3/3/1→1/1/1 (v/v/v)) to give7-4 (200 mg, 72%) as a white amorphous solid.

[0375] 1H-NMR (CDCl3) was consistent with the proposed title structure.FABMS: 420 (M+H)

EXAMPLE 81-Dimethylcarbamoyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxamide800

[0376]

[0377] Step 1: Preparation of Compound 8-2

[0378] To a solution of 8-1 (400 mg, 1.30 mmol) in DMF (3 mL), was addedNaH (62 mg, 2.60 mmol, washed with dry n-hexane before use), and themixture was stirred at room temperature for 30 min. Dimethyl carbamoylchloride (0.18 mL, 1.95 mmol) was added to the mixture, and the reactionmixture was stirred at room temperature for 24 h. The mixture wasdiluted with ethyl acetate, washed with saturated NaHCO₃ and brine,dried (MgSO₄), and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane/ethyl acetate1/1→1/2→1/4 (v/v)) to give 8-2 (535 mg) as a crude product.

[0379] Step 2 Preparation of Compound 8-3

[0380] To a solution of 8-2 (535 mg, 1.36 mmol) in EtOH/THF (3 mL/1 mL)was added 20% Pd(OH)₂-C (200 mg). The resulting mixture was stirredunder H₂ at room temperature overnight. The catalyst was filtrated off,and the filtrate was concentrated under reduced pressure to give 8-3(320 mg, 95%, two steps).

[0381] Step 3: Preparation of Compound 800

[0382] Compound 8-3 (300 mg, 1.16 mmol) was dissolved in CHCl₃ (3 mL),and Et₃N (0.44 ml, 3.15 mmol) and phenyl5-phenyl-1,3,4-thiadiazol-2-ylcarbamate (317 mg, 1.05 mmol) were added.The resulting mixture was stirred under reflux overnight. The reactionmixture was cooled to room temperature and extracted with CHCl₃, whichwas washed with a saturated NaHCO₃ and brine. The organic layer wasdried (MgSO₄) and concentrated under reduced pressure. The residue wastriturated with Et₂O to give 800 (334 mg, 69%) as a white solid. m.p.:267° C.

[0383] 1H-NMR (CDCl3) was consistent with the proposed title structure.FABMS: 463 (M+H)

[0384] Compounds, in which X is carbon atom and Z is nitrogen atom inthe following general formula, are generally prepared according toExample 9.

EXAMPLE 91-Acetyl-N-(3-guinolinyl)spiro[indoline-3,4′-cyclohexane]-1′-carboxamide900

[0385]

[0386] Step 1: Preparation of Compound 9-1

[0387] A mixture of terephthalic acid monomethylester (40.0 g, 0.222mol) and 5% Rh-C (wet) (40 g) in 1,4-dioxane (200 mL) and MeOH (160 mL)was stirred under H₂ at 50 atm for 18 h. The catalyst was then filteredoff and the filtrate was concentrated to give 41.0 g (99%) of 9-1.

[0388] Step 2: Preparation of Compound 9-2

[0389] To a stirred solution of 41.0 g (0.220 mol) of 9-1 in THF (200mL) cooled at 0° C. was added 27.4 mL (0.289 mol) of Me₂S.BH₃. Thesolution was stirred at room temperature for 3 h and AcOH (6 mL) wasadded. The resulting mixture was diluted with H₂O and extracted withEtOAc. The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated to give 36.1 g (95%) of 9-2.

[0390] Step 3: Preparation of Compound 9-3

[0391] To a stirred mixture of Celite (10 g) and 9-2 (3.00 g; 17.4 mmol)in CH₂Cl₂ (60 mL) was added PCC (11.3 g; 52.3 mmol). The mixture wasstirred at room temperature for 3 h and diluted with hexane (100 mL).The resulting mixture was then filtered and the filtrate wasconcentrated to give 9-3 (2.65 g; 90%).

[0392] Step 4: Preparation of Compound 9-4

[0393] To a stirred solution of 9-3 (2.65 g; 15.6 mmol) in 35 mL ofPhMe-MeCN (39:1) cooled at 0° C. were added phenylhydrazine (1.54 mL;15.6 mmol) and TFA (3.61 mL; 46.8 mmol). The mixture was stirred at roomtemperature for 16 h and MeOH (35 mL) was added. The mixture was cooledto 0° C. and NaBH₄ (885 mg; 23.4 mmol) was added and stirred at 0° C.for 1 h. The reaction mixture was poured into sat. NaHCO₃ and extractedwith EtOAc. The organic layer was washed with H₂O and brine, dried(Na₂SO₄), and concentrated to give the crude product 9-4 (3.60 g).

[0394] Step 5: Preparation of Compound 9-5 and 9-6

[0395] To a stirred solution of crude product 9-4 in THF (50 mL) cooledat 0° C. were added Et₃N (6.52 mL; 46.8 mmol) and AcCl. (2.22 mL; 31.2mmol) The mixture was stirred at 0° C. for 1 h then poured into 10%citric acid. The resulting mixture was extracted with EtOAc. The organiclayer was washed with sat. NaHCO₃ and brine, dried (Na₂SO₄), andconcentrated. The residual oil was purified by silica gel columnchromatography (100 g, hexane-EtOAc 3:1→2:1→4:3) to give 577 mg of 9-5(14%) and 1.42 g of the mixture of 9-5 and 9-6 (33%).

[0396] Step 6: Preparation of Compound 9-7 and 9-8

[0397] To a stirred solution of 9-6 (1.42 g; 5.20 mmol) in MeOH (20 mL)was added 4N NaOH (5.2 mL; 20.8 mmol). The solution was stirred at roomtemperature for 3 h and the MeOH was concentrated. 1N HCl (30 mL) wasadded and extracted with EtOAc. The organic layer was washed with brine,dried (Na₂SO₄), and concentrated. The residual oil was purified bysilica gel column chromatography (80 g, CHCl₃-MeOH 1:0 200:1 100:1) togive 367 mg of 9-7 (26%) and 627 mg of 9-8 (44%).

[0398] Step 7: Preparation of Compound 900

[0399] To a stirred solution of 20 mg (73.3 mmol) of 9-7 (20 mg; 73.3mmol) and 3-aminoquinoline (21 mg; 73.3 mmol) in pyridine (0.5 mL) wasadded WSC.HC (21 mg; 101 mmol. The mixture was stirred at 50° C. for 1h. The reaction mixture was poured into H₂O and extracted with EtOAc.The organic layer was washed with H₂O and brine, dried (Na₂SO₄), andconcentrated. The residual oil was purified by silica gel columnchromatography (5 g, hexane-EtOAc-MeOH 1:1:0→8:8:1→6:6:1→4:4:1) to give900 (17.0 mg; 58%) as a colorless amorphous solid.

[0400] 1H-NMR (DMSO-d6) was consistent with the proposed titlestructure. FABMS: 400 (M+H)

[0401] The following compounds #901-#905 were prepared from theappropriate amines in analogy to the procedure of Example 9.

[0402] #901

[0403]trans-N-(4-biphenylyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 119.8-120.5° C.

[0404] #902

[0405]trans-1-methylsulfonyl-N-[4-(3-pyridyl)phenyl]spiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 212.5-213.0° C.

[0406] #903

[0407]trans-1-methylsulfonyl-N-(5-phenylpyrrazol-3-yl)spiro[indoline-3,4-cyclohexane]-1′-carboxamidem.p.: 212-213° C.

[0408] #904

[0409]trans-N-[1-(3,5-difluorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 287-292° C.

[0410] #905

[0411]trans-N-[1-(4-fluorophenyl)imidazol-4-yl]-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 264-266° C.

EXAMPLE 102,3-Dihydro-1-methanesulfonyl-N-(5-phenyl-pyrazinyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamide1000

[0412]

[0413] Step 1: Preparation of Compounds 10-2 and 10-3

[0414] Indene 10-1 was synthesized by the method described in U.S. Pat.No. 5,536,716

[0415] To a solution of indene 10-1 (9.82 g, 34.4 mmol) in THF (100 mL)was slowly added 2M BH₃.SMe₂ in THF (24.1 mL, 48.2 mmol) at 0°. Afterbeing stirred for 4 h at 0°, the mixture was treated with 2N NaOH (100mL) and 30% H₂O₂ (25 mL) for 30 min at 0°. The organic layer wasseparated and the aqueous layer was extracted with ether (100 mL×2). Thecombined organic layer was washed with 5% Na₂S₂O₃ aqueous and brine,dried (Na2SO4), and was evaporated off. The residue was purified bysilica gel column chromatography hexane/ethyl acetate (600 mL 4/1→2/1)to give 10-2 (4.83 g, 46%) as an amorphous solid and its regioisomer10-3 (5.02 g, 48%) as a solid.

[0416] Step 2: Preparation of Compound 10-4

[0417] To a solution of alcohol 10-2 (4.83 g, 15.9 mmol) in CHCl₃ (70mL) and triethylamine (6.65 mL) was slowly added methanesulfonylchloride (2.46 mL) at 0°. The mixture was stirred for 15 min and wasdiluted with Et₂O. The organic layer was washed with aqueous NH₄Cl,saturated aqueous NaHCO₃ and brine, dried (Na₂SO₄) and concentrated invacuo.

[0418] The residue was dissolved in DMF (40 mL) and sodium thiomethoxide(2.23 g, 31.8 mmol) was added to the solution. After being stirred for50 min at room temperature, the resulting mixture was poured into water,and extracted with Et₂O, and washed with water and brine. The organiclayer was dried (Na₂SO₄) and concentrated in vacuo.

[0419] The residue was dissolved with CHCl₃ (100 mL) and MCPBA (10.3 g,47.7 mmol) was added to the solution at 0°. After being stirred for 20min at 0°, to the suspension was added aqueous Na₂S₂O₃ and aqueousNaHCO₃. The mixture was extracted with Et₂O, and washed with saturatedNaHCO₃ aqueous twice and brine. The organic layer was dried (MgSO₄), andconcentrated in vacuo. The residue was purified by silica gelchromatography (Merck 7734, 300 mL, Hexane/ethyl acetate=1/1) to give5.33 g (92%) of sulfone 10-4.

[0420] Step 3: Preparation of Compound 10-5

[0421] Sulfone 10-4 (5.27 g) was dissolved in ethyl acetate (50 mL) andthe solution was treated with 4N HCl in ethyl acetate (10 mL) at 0°.After being stirred for 2.5 hr. at room temperature, to the mixture wasagain added 4N HCl in ethyl acetate (10 mL). After being stirred for 2.5h, the resulting mixture was evaporated and the residue was suspended inethyl acetate and collected to give amine HCl salt 10-5 (3.72 g; 85%) asa white solid.

[0422] Step 4: Preparation of Compound 1000

[0423] Amine HCl salt 10-5 (160 mg) and phenoxy compound 10-6 (153 mg,0.53 mmol) were suspended in CHCl₃ (3.0 mL) and triethylamine (0.16 mL),and the suspension was refluxed for 3 h. The resulting mixture wascooled to room temperature. After diluting with ethyl acetate, theorganic layer was washed with NH₄Cl aqueous, saturated aqueous NaHCO₃and brine. The organic layer was dried (Na₂SO₄) and concentrated invacuo. The residue was suspended with ethyl acetate and IPE, andcollected to give urea 1000 (177 mg) as a solid.

[0424] The following compounds were prepared by the proceduresdeesdcribed in Example 10 procedure of Example 10.

[0425] #1001

[0426]2,3-dihydro-1-methylsulfonyl-N-(4-phenyl-2-oxazolyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamideamorphous solid.

[0427] 1H-NMR (CDCl3) δ ppm: 1.79-1.87 (2H, m), 2.00-2.10 (2H, m), 2.42(1H, dd, J=14.5 Hz, 6.5 Hz), 2.75 (1H, dd, J=14.5 Hz, 9.6 Hz), 2.80 (3H,s), 2.99-3.09 (2H, m), 4.56-4.61 (2H, m), 4.72 (1H, dd, J=9.6Hz, 6.5Hz), 7.21 -7.49 (10H, m), 7.69 (1H, d, J 7.6 Hz).

[0428] #1002

[0429] 2,3-dihydro-1-methylsulfonyl-N-[3-(3-chlorophenyl)-5-isoxazolyl)spiro[1H-indene-3,4′-piperidine]-1′-carboxamide amorphoussolid.

[0430] 1H-NMR ((CD3)2CO) δ ppm: 1.89-2.06 (4H, m), 2.74 (1H, dd, J=14.3Hz, 6.2 Hz), 2.79 (1H, dd, J=14.3 Hz, 9.3 Hz), 2.96 (3H, s), 3.20-3.23(2H, m), 4.30-4.35 (2H, m), 4.94 (1H, dd, J=9.3 Hz, 6.2 Hz), 6.63 (1H,s), 7.29-7.34 (1H, m), 7.38-7.40 (2H, m), 7.52-7.54 (2H, m), 7.66 (1H,d, J=7.5 Hz), 7.81-7.84 (1H, m), 7.89 (1H, d, J=1.2 Hz), 9.50 (1H, s).

EXAMPLE 11

[0431] 2,3-Dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-pipendine]-1-carboxamide 1100

[0432] Step 1: Preparation of Compound 11-2

[0433] To a solution of alcohol 11-1 (1.05 g, 3.46 mmol) in CHCl₃ (15mL) and triethylamine (1.45 mL, 10.4 mmol) was added methanesulfonylchloride (0.535 mL, 6.92 mmol) at 0°. The mixture was stirred for 15 minand was diluted with Et₂O. The organic layer was washed with NH₄Claqueous, aqueous saturated NaHCO₃ and brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was dissolved in DMSO (15 mL) andpotassium thioacetate (395 mg, 31.1 mmol) was added to the solution.After being stirred for 1.5 h at room temperature, the resulting mixturewas poured into water and extracted with Et₂O. The organic layer waswashed with water and brine, dried (Na₂SO₄), and concentrated in vacuo.The residue was purified by a silicagel chromatography (WAKO C-200,Hexane/ethyl acetate=8/1→5/1) to give thioacetate 11-2 (1.05 g; 89%).

[0434] Step 2: Preparation of Compound 11-3

[0435] Thioacetate 11-2 (222 mg, 0.614 mmol) was dissolved in ethylacetate (2.0 mL) and the solution was treated with 4N HCl in ethylacetate (5.0 mL). After being stirred for 3.5 h. at room temperature,the resulting mixture was evaporated and the residue was co-evaporatedthree times with CHCl₃, was diluted and collected to give amine HCl salt11-3 (201 mg, quant.) as an amorphous solid.

[0436] Step 3: Preparation of Compound 11-5

[0437] Amine HCl salt 11-3 (201 mg, 0.614 mmol) and phenoxy compound11-4 (176 mg; 0.608 mmol) were suspended in CHCl₃ (6.0 mL) andtriethylamine (0.200 mL), and the suspension was refluxed for 3 h. Theresulting mixture was cooled to room temperature. After diluting withethyl acetate, the organic layer was washed with aqueous NH₄Cl,saturated aqueous NaHCO₃ and brine. The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The residue was suspended with ethanoland collected to give urea 11-5 (235 mg; 84%) as a solid.

[0438] Step 4: Preparation of Compound 11-6

[0439] Urea 11-5 (200 mg) was dissolved in methanol (3.0 mL) and THF(3.0 mL) and the solution was treated with 2N NaOH aqueous (3.0 mL) at60° for 1.5 h. The resulting mixture was poured into water and extractedwith ethyl acetate, and washed with brine. The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was suspended with ethylacetate and hexane, and collected to give thiol 11-6 (155 mg; 85%) as awhite solid.

[0440] Step 5: Preparation of Compound 1100

[0441] To the solution of thiol 11-6 (79.5 mg) in anhydrous methanol(3.0mL) was added sodium methoxide (31.1 mg) and methyl iodide (0.036mL). After being stirred for 12 h at room temperature, the resultingmixture was diluted with ethyl acetate and washed with water and brine.The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Theresidue was triturated with IPE to give methylthio compound 1100 (72.6mg; 88%) as a white solid.

EXAMPLE 122,3-Dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide1200

[0442]

[0443] To a solution of2,3-dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide(1100, 55.4 mg, 0.129 mmol) in methanol (3.0 mL), THF (2.0 mL) and H₂O(1.0 mL) was added sodium meta periodade (34.6 mg, 0.161 mmol). Afterbeing stirred for 35 h at room temperature, the resulting mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried (Na₂SO₄), and concentrated invacuo. The residue was triturated with ethyl acetate and isopropyl etherto give2,3-dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide45.4 mg; 79%) as an amorphous solid, 1200.

[0444] 1H-NMR (CDCl3) δ ppm: 1.90-2.10 (4H, m), 2.30-2.50 (1H, m), 2.50-2.70 (0.5 H, m), 2.48 (1.5H, s), 2.55 (1.5H, s), 2.73-2.82 (0.5H, m),3.05-3.30 (2H, m), 4.00-4.30 (2H+0.5H, m), 4.39-4.47 (0.5H, m),6.55-6.67 (0.5H, brs), 6.67-6.80 (0.5H, brs), 7.20-7.60 (13H, m). FABMS:446 (M+H)

EXAMPLE 134-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride, 1300

[0445]

[0446] Step 1. Preparation of4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine(13-1)

[0447] A solution of 3-chloro-2-pyridylacetonitrile [prepared by themethod described in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) wasslowly added to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and themixture was stirred at room temperature for 1 h. A solution ofN,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO(19 mL) was added, and the resulting mixture was stirred at 75° C. for 4h. After cooling, water (100 mL) was added, and the mixture wasextracted with ethyl acetate. The organic extract was washed with brine,dried (Na₂SO4), and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/2) to give4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine1(1.91 g, 60%) as an orange oil.

[0448] Step 2. Preparation of4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (13-2)

[0449] A mixture of4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine (1.91g, 5.59 mmol) and lithium tri-tert-butoxyaluminohydride (1 M solution inTHF, 22 mL) in 1,4-dioxane (28 mL) was stirred at 125° C. overnight in asealed tube. After cooling, 1 N aqueous NaOH solution (50 mL) and ethylacetate were added to the mixture, and the mixture was filtered throughCelite. The organic layer was separated and washed with brine, dried(NaSO4), and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=7/3→chloroform/methanol=9/1) to give4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (2)(0.80 g, 46%) as an orange solid.

[0450] Step 3. Preparation of4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-Piperidine](13-3)

[0451] To a suspension of4-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (0.80 g,2.59 mmol) in ethyl acetate (13 mL) were added Et₃N (1.08 mL, 7.77 mmol)and methylsulfonyl chloride (0.24 mL, 3.1 mmol) at 0° C., and themixture was stirred at the same temperature for 1.5 h. The mixture wasdiluted with ethyl acetate, washed with brine and dried (NaSO4). Thesolvent was evaporated in vacuo, and the residue was purified by silicagel column chromatography (chloroform/methanol=99/1) to give4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](476 mg, 47%).

[0452] Step 4. Preparation of4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (13-4)

[0453] A mixture of4-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](476 mg, 1.23 mmol), cyclohexene (3 mL) and 10% Pd/C (500 mg) in ethanol(12 mL) and THF (12 mL) was refluxed for 5 h. The catalyst was removedby filtration, and the filtrate was concentrated under reduced pressure.Purification of the residue by column chromatography on alumina(chloroform/methanol=9/1) gave4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (102 mg, 31%).

[0454] Step 5. Preparation of4-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride, 1300

[0455] A mixture of4-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (100 mg, 0.37mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (108 mg, 0.37 mmol) andEt3N (0.26 mL, 1.87 mmol) in CHCl3 (1.9 mL) was refluxed for 1.5 h.After cooling, the mixture was diluted with EtOAc, washed with aqueoussaturated NaHCO3 and brine, dried over MgSO4, and concentrated underreduced pressure. The residue was dissolved in chloroform, and 4 NHCl/ethyl acetate (0.38 mL) was added. The solvent was evaporated, andthe residue was crystallized from methanol, chloroform and diisopropylether to give4-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamidehydrochloride (143 mg, 76%) as a brown powder. m.p.: 138-145° C.

[0456] 1H-NMR (CDCl3) was consistent with the proposed title structure.FABMS: 465 (M+H)

EXAMPLE 147-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,(1400)

[0457]

[0458] Step 1. Preparation of 4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine (14-1)

[0459] A solution of 2-chloro-3-pyridylacetonitrile [prepared by themethod of Bremner, et al, Synthesis, 1992, 6, 528-530] (2.14 g, 14.0mmol) in DMSO (28 mL) was slowly added to NaH (60% in oil, 1.51 g, 37.8mmol), and the mixture was stirred at room temperature for 1 h. Asolution of N,N-bis(2-chloroethyl)-p-methoxybenzylamine (3.67 g, 14.0mmol) in DMSO (28 mL) was added, and the resulting mixture was stirredat 75° C. for 4 h. After cooling, the mixture was partitioned betweenwater and ethyl acetate, and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with 1 N aqueous NaOHsolution and brine, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate 9/1→1/1) to give4-(2-chloro-3-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1(1.62 g, 34%) as a brown solid.

[0460] Step 2. Preparation of7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (14-2)

[0461] A mixture of4-(2-chloro-3-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine (1.62g, 4.74 mmol) and lithium tri-tert-butoxyaluminohydride (1 M solution inTHF, 19 mL) in 1,4-dioxane (24 mL) was stirred at 130° C. overnight in asealed tube. After cooling, 1 N NaOH (50 mL) and EtOAc were added to themixture, and the mixture was filtered through Celite. The organic layerwas separated and washed with brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate 4/1→chloroform/methanol 9/1) togive 7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (2)(0.96 g, 66%) as a brown solid.

[0462] Step 3. Preparation of7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspirorindoline-3,4′-piperidine](14-3)

[0463] To a suspension of7-aza-1′-(4-methoxyphenyl)methylspiro[indoline-3,4′-piperidine] (0.96 g,3.10 mmol) in EtOAc (16 mL) were added Et₃N (1.30 mL, 9.30 mmol) andmethylsulfonyl chloride (0.36 mL, 4.65 mmol) at 0° C., and the mixturewas stirred at the same temperature for 2 h. The mixture was dilutedwith EtOAc, washed with brine and dried (Na₂SO₄). The solution waspassed through a pad of silica gel and the pad was washed with ethylacetate. The filtrate and washing were combined, and the solvent wasevaporated to give7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](0.99 g, 82%) as a brown amorphous solid.

[0464] Step 4. Preparation of7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (14-4)

[0465] A mixture of7-aza-1′-(4-methoxyphenyl)methyl-1-methylsulfonylspiro[indoline-3,4′-piperidine](0.82 g, 2.12 mmol), cyclohexene (5 mL) and 10% Pd/C (0.82 g) in EtOH(20 mL) and THF (20 mL) was refluxed for 2 h. The catalyst was removedby filtration, and the filtrate was concentrated under reduced pressure.The residue was reprecipitated from MeOH, EtOAc and IPE to give7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (0.47 g, 83%) as abrown powder.

[0466] Step 5. Preparation of7-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,1400

[0467] A mixture of7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] (134 mg, 0.50mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (116 mg, 0.45 mmol) andEt3N (0.35 mL, 2.5 mmol) in CHCl3 (2.5 mL) was stirred at 90° C. in asealed tube for 1.5 h. After cooling, the mixture was diluted withEtOAc, washed with NaHCO3 and brine, dried (Na₂SO₄), and concentratedunder reduced pressure. Purification of the residue by columnchromatography on silica gel (hexane/ethylacetate=7/3→chloroform/methanol=9/1) gave7-aza-1-methylsulfonyl-N-(5-phenyl-2-pyrazinyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide(181 mg, 78%) as a white powder. m.p.: 214-215° C.

[0468] 1H-NMR (CDCl3) was consistent with the proposed title structure.FABMS: 465 (M+H)

[0469] Compound #1401 and #1402 were prepared from7-aza-1-methylsulfonylspiro[indoline-3,4′-piperidine] and phenylN-(4-benzoylphenyl)carbamate or phenylN-(3-phenyl-5-isoxazolyl)carbamate, respectively, according to theprocedure described in Example 14.

[0470] #1401

[0471]7-aza-N-(4-benzoylphenyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidepale yellow amorphous solid.

[0472] 1H-NMR (DMSO-d6) δ ppm: 1.69-1.90 (4H, m), 3.02-3.12 (2H, m),3.29 (3H, s), 3.97 (2H, s), 4.05-4.20 (2H, m), 7.00 (1H, dd, J=7.5, 5.0Hz), 7.50-7.80 (10H, m), 8.12 (1H, dd, J=5.0, 1.4 Hz), 9.0 (1H, brs).

[0473] #1402

[0474]7-aza-N-(3-phenyl-5-isoxazolyl)-1-methylsulfonylspiro[indoline-3,4′-piperidine]-1′-carboxamidem.p.: 211-212° C.

EXAMPLE 15 1-Methylsufonyl-N-(4-ethoxycarbonylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide 1500

[0475]

[0476] To a stirred solution of1-methylsulfonyl-spiro[indoline-3,4′-piperidine] (2.66 g, 10 mmol) indichloromethane (50 mL), was added ethyl 4-isocyanatobenzoate (1.91 g,10 mmol) at room temperature. The resulting solution was stirred forfour hours during which time precipitation occurred. The mixture wasevaporated to remove dichloromethane, and then was suspended in methanol(20 mL), filtration followed by washing with cold methanol gave 1500 asa white solid (4.56 g, 100%)

[0477] NMR (CDCl3, 300 MHz): δ ppm 8.00 (d, J=8.8 Hz, 2H); 7.46 (d,J=8.8 Hz, 2H); 7.43-7.06 (m, 4H); 6.62 (s, 1H), 4.36 (q, J=7 Hz, 2H),4.14 (br. D, J=13 Hz, 2H); 3.90 (s, 2H), 3.09 (dt, J=1, 13 Hz, 2H); 2.94(s, 3H), 2.00 (dt, J=4, 13 Hz, 2H), 1.82 (br. d, J=13Hz, 2H), 1,38 (t,J=7 Hz, 3H). ESI-MS: 458 (M+1)

[0478] The following compounds were similarly prepared from1-methylsulfonyl-spiro[indoline-3,4′-piperidine] and the appropriateisocyanates.

[0479] #1501

[0480]1-methylsufonyl-N-(4-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0481] #1502

[0482]1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 428 (M+1);

[0483] #1503

[0484]1-methylsufonyl-N-(4-methylthiophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0485] #1504

[0486]1-methylsuonyl-N-(3,4-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 454 (M+1);

[0487] #1505

[0488]1-methylsufonyl-N-(4-phenylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 462 (M+1);

EXAMPLE 161-Methylsufonyl-N-(4-(2-hydroxyethyl)phenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide1600

[0489]

[0490] To a stirred solution of1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide(400 mg) in ethanol/dichloromethane (5/5 mL) at 0° C., was added sodiumborohydride (100 mg). The mixture was stirred for 1 hour, then 3 N HCl(0.2 mL) was added to destroy the excess hydride. The mixture was thenconcentrated and partitioned between water and dichloromethane. Theorganic layer was dried over MgSO4 and evaporated to give the titlecompound, 1600 as white powder (386 mg). ESI-MS: 430 (M+1)

EXAMPLE 171-Sulfamoyl-N-(3,4-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide1700

[0491]

[0492] This compound was prepared from1-sulfamoylspiro[indoline-3,4′-piperidine] (L. Guo, A. Patchett, L.Yang, U.S. Pat. No. 5,783,582, Jul. 21, 1998.) and 3,4-dichlorophenylisocyanate by the same procedures described in Example 15

[0493] NMR (DMSO-d6, 400 MHz): δ ppm: 8.84 (s, 1H), 7.87 (s, 1H), 7.47(s, 2H), 7.31-7.25 (m, 4H), 7.18 (t, J=7.6 Hz, 1H), 6.98 (t, J=7.6 Hz,1H), 4.13 (d, J=13.6 Hz, 2H), 3.81 (s, 2H), 3.02-2.94 (m, 2H), 1.79-1.74(m, 2H), 1.65 (d,J=13.2 Hz, 2H). ESI-MS: 455 (M+1)

[0494] Employing substantially the same procedure as described inExample 15, the following compounds were prepared from1-sulfamoyl-spiro[indoline-3,4′-piperidine] and the appropriateisocyanate.

[0495] #1701

[0496]1-Sulfamoyl-N-(4-ethoxycarbonylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 459 (M+1);

[0497] #1702

[0498]1-Sulfamoyl-N-(4-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1);

[0499] #1703

[0500]1-Sulfamoyl-N-(3,4-dimethylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 415 (M+1);

[0501] #1704

[0502]1-Sulfamoyl-N-(2,4-dimethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 447 (M+1);

[0503] #1705

[0504]1-Sulfamoyl-N-(2,6-dichlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 455 (M+1);

[0505] #1706

[0506]1-Sulfamoyl-N-(3-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1)

[0507] #1707

[0508]1-Sulfamoyl-N-(4-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

[0509] #1708

[0510]1-Sulfamoyl-N-(2-chlorophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 421 (M+1);

[0511] #1709

[0512]1-Sulfamoyl-N-(3-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

[0513] #1710

[0514]1-Sulfamoyl-N-(2-nitrophenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 432 (M+1);

[0515] #1711

[0516]1-Sulfamoyl-N-(4-ethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0517] #1712

[0518]1-Sulfamoyl-N-(2-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0519] #1713

[0520]1-Sulfamoyl-N-(4-phenyloxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 479 (M+1);

[0521] #1714

[0522]1-Sulfamoyl-N-(4-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 417 (M+1);

[0523] #1715

[0524]1-Sulfamoyl-N-(3-methoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0525] #1716

[0526]1-Sulfamoyl-N-(3-ethoxyphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 431 (M+1);

[0527] #1717

[0528]1-Sulfamoyl-N-(4-isopropylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 429 (M+1);

[0529] #1718

[0530]1-Sulfamoyl-N-(2-ethylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 415 (M+1);

[0531] #1719

[0532]1-Sulfamoyl-N-(4-methylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

[0533] #1720

[0534]1-Sulfamoyl-N-(3-methylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

[0535] #1721

[0536]1-Sulfamoyl-N-phenyl-spiro[indoline-3,4′-piperidine]-1′-carboxamide,ESI-MS: 401 (M+1);

[0537] #1722

[0538]1-Sulfamoyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamideESI-MS: 429 (M+1);

EXAMPLE 18trans-N-(5-acetyl-2-pyrimidinyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamide(#1800)

[0539]

[0540] Pyridine (0.121 mL, 1.50 mmol) andtrans-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] (92.8 mg, 0.330 mmol) wereadded to a solution of 2-chloro-1,3-dimethylimidazolium chloride (152mg, 0.90 mmol) in CHCl₃ (0.800 mL) and THF (0.800 mL). After stirringfor 5 min at room temperature, 2-amimo-5-acetylpyrimidine was added tothe mixture. The resulting mixture was stirred at room temperature for2.5 h. The mixture was diluted with EtOAc, washed with 5% KHSO₄, sat.NaHCO₃ and brine, dried (MgSO₄). After removal of the solvent, theresidue was purified by column chromatography on silica gel(CHCl₃/MeOH=100/0→99/1) to give an oil, which was triturated withEtOAc-hexane to give 1800 (93.8 mg, 56%) as a white powder. m.p.:100-105° C.

[0541] Compounds #1801-1803 were prepared from 2-amino-5-acetylpyrazinein analogy to the procedure of Example 10.

[0542] #1801trans-N-(5-acetyl-2-pyrazinyl)-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 220.8-221.2° C.

[0543] The following compounds #1802-#1803 were prepared from6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] and the appropriate amines inanalogy to the procedure of Example 10.

[0544] #1802

[0545]trans-N-(5-acetyl-2-pyrimidinyl)-6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 196-198° C.

[0546] #1803

[0547]trans-N-(5-acetyl-2-pyrazinyl)-6-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 228.1-228.3° C.

[0548] The following compounds #1804-#1805 were prepared from5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxylicacid [prepared by the method of Example 9] and the appropriate amines inanalogy to the procedure of Example 10.

[0549] #1804

[0550]trans-N-(5-acetyl-2-pyrimidinyl)-5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 210.5-211.7° C.

[0551] #1805

[0552]trans-N-(5-acetyl-2-pyrazinyl)-5-fluoro-1-methylsulfonylspiro[indoline-3,4′-cyclohexane]-1′-carboxamidem.p.: 209.3-209.6° C.

EXAMPLE 19 Determination of IC₅₀

[0553] LMtk-cells expressing human Y5 receptors were washed with 50 mMHEPES buffer (pH 7.4) containing 20% sucrose, homogenized andcentrifuged at 1,000×g for 15 min. The supernatant was centrifuged at100,000×g for 45 min. The pellets were resuspended in 5 mM HEPES buffer(pH 7.4) and centrifuged again. The membrane fraction was resuspended bya homogenizer in the same buffer and used for this study.

[0554] Binding of [¹²⁵I]PYY to the membrane was performed in 0.2 ml of25 mM Tris buffer (pH 7.4) containing 10 mM MgCl₂, 1 mM PMSF, 0.1%bacitracin and 0.5% BSA. The membranes (100-300 μg/ml) were incubated at25° C. for 120 min with [¹²⁵I]PYY (25 pM). Bound and free peptides wereseparated by filtration using a GF/C glass filter (Whatman, England)presoaked with 0.3% polyethylenimine. The remaining radioactivity on thefilter was quantitated using a Cobra™ (Packard, Japan). Specific bindingof [¹²⁵I]PYY was defined as the difference between total binding andnonspecific binding in the presence of 1 μM PYY.

[0555] Employing the procedure described in Example 18, a representativenumber of the compounds of this invention were found to have IC50 valuesless than 1 mM.

[0556] Using procedures similar to those described in Example 18, inwhich membranes expressing other NPY subtypes are used in place of theY5 membranes, many of the compounds of this invention have greatselectivity for the Y5 receptor over the NPY Y1, Y2 and Y4 receptors.For example, many of the compounds of this invention have IC50>1000 nMon Y1, Y2 and Y4 receptors.

EXAMPLE 20 Effect of Compound 100 on Bovine Pancreatic Polypeptide(bPP)-induced Food Intake in Spraque-Dawley Rats

[0557] Materials and Methods

[0558] Male Sprague-Dawley rats aged 7 weeks (Charles River, Japan) weremaintained under the controlled temperature (23±3° C.), humidity(55±15%) and light-dark cycle (7:00-19:00 light on). Rats were housedindividually with ad libitum access food (CE-2, Clea Japan) and tapwater.

[0559] Rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.,Dainabot, Japan). A permanent stainless steel guide cannula forintracerebroventricular (ICV) injection (21 gauge, 10 mm long) wasstereotaxically implanted into the right lateral ventricle. Thestereotaxic coordinates used were as follows: 0.9 mm posterior and 1.2mm lateral to the bregma and 1.5 mm ventral to the brain surface.

[0560] Animals were allowed at least 6-day recovery postoperativelybefore the start of feeding experiment. The day before the experiment,they were handled and underwent mock injection, and nocturnal foodintake was measured. Rats which ate more than 15 g during the nightbefore the experiment were used for the following experiment.

[0561] Test compounds were suspended in 0.5% methylcellulose and orallyadministered by gavage. Administration of test compounds usually beganat 10:00. Dosing volume was 5 ml/kg. One hour after the drugadministration, bovine pancreatic polypeptide (PP, 5 g/10 l/1 min) wasICV injected through a stainless steel injector (26 gauge) attached to a50 l Hamilton microsyringe by polyethylene tubing. The injector extended2 mm beyond the end of the guide cannula. Bovine PP was dissolved in 10mM PBS containing 0.05% BSA. Two hour post-injection food intake wasmeasured for each rat.

[0562] Results

[0563] Compound 100 was orally administered 1 hour prior to theICV-injection of bPP in satiated male Sprague-Dawley rats. Compound 100(1, 3, 10 and 30 mg/kg) suppressed bPP-induced food intake in adose-dependent manner, and the minimum effective dose is estimated to be3 mg/kg. Furthermore, this compound at 100 mg/kg, p.o. did not cause anyabnormal behavior in rats and mice during 24 hour after dosing. Thus,Compound 100 has a potent in vivo Y5 antagonistic activity withoutcausing any abnormal behavior.

EXAMPLE 21A

[0564] Tablets containing 1-25 mg of compound Amount mg Compound offormula I 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5Magnesium stearate 0.5 0.5 0.5

EXAMPLE 21B

[0565] Tablets containing 26-100 mg of compound Amount mg Compound offormula (I) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5Magnesium stearate 0.5 0.5 0.5

What is claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein; V, W, X and Zare independently selected from CH and N; R¹ is H, C₁₋₃ alkyl, C₁₋₃alkoxy, F, or Cl; R² is S(O)n R⁶, COR6 or CHO, wherein n is 0, 1 or 2;and R⁶ is N(R³)₂ or C₁₋₃ alkyl; R³ is independently H or C₁₋₃ alkyl; Aris aryl or heteroaryl; R⁴ and R⁵ are independently selected from: (1)hydrogen, (2) aryl, either unsubstituted or substituted with (a) halo(b) C₁₋₃ alkoxy, (c) —N(C₁₋₃ alkyl)₂, (d) C₂₋₄ alkanoyl, or (e) aryl;(3) nitro, (4) C₁₋₅ alkyl, (5) C₁₋₅ alkoxy, (6) hydroxy-C₁₋₃ alkyl, (7)carboxy, (8) halo, (9) C₁₋₅ alkylthio, (10) C₁₋₅ alkoxycarbonyl, (11)pyridylcarbonyl, (12) benzoyl, (13) phenyl-C₁₋₃alkoxy, (14) pyridyl,either unsubstituted or substituted with C₁₋₃ alkyl or C₁₋₃ alkoxy, (15)C3-6 cycloalkyl, (16) oxazolyl, (17) thiazolyl, (18) triazolyl, (19)phenoxy or (20) C₂₋₆ alkanoyl.
 2. The compound of claim 1 wherein Ar isphenyl, of structural formula I(a)

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2 wherein X and Z are both nitrogen and V and W are both —CH═.
 4. Thecompound of claim 3 wherein R² is —SO₂(C₁₋₃ alkyl) or SO₂NH₂.
 5. Thecompound of claim 4 wherein R⁴ and R⁵ are independently selected from:phenyl, pyridyl, benzoyl, halophenyl, phenoxy, C₁₋₅ alkylpyridyl,benzhydryl, phenyl-C₁₋₃ alkoxy, NO₂, C₂₋₄ alkanoyl, halo, C₁₋₅ alkoxy,C₁₋₃ alkoxycarbonyl, C₁₋₅ alkylthio, triazolyl, carboxy, hydrogen, C₁₋₅alkyl, pyridylcarbonyl, and C₁₋₃ alkoxyphenyl.
 6. The compound of claim5 or a pharmaceutically acceptable salt thereof selected from thosedepicted in the following Table:


7. The compound of claim 1 wherein Ar is a 5- or 6-membered heteroarylhaving, besides carbon atoms, 1 to 3 hetero atoms selected from N, O orS as atoms constituting the ring, or benzo- or pyrido-fused versionsthereof of structural formula I(b);

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim7 wherein X and Z are both nitrogen and V and W are both —CH═.
 9. Thecompound of claim 8 wherein R² is —SO₂(C₁₋₃ alkyl) or —SO₂N(C₁₋₃alkyl)₂.
 10. The compound of claim 9 wherein the heteroaryl group, Ar,is selected from: thiazolyl, thiadiazolyl, pyrazolyl, pyridyl,benzothiazolyl, oxazolyl, pyridothiazolyl, benzoxazolyl, quinolyl,pyrazinyl, thienyl, isoxazolyl, pyrimidinyl, benzimidazolyl, oxadiazolyland imidazolyl.
 11. The compound of claim 10, or a pharmaceuticallyacceptable salt thereof, selected from those depicted in the followingTable:


12. The compound of claim 1 wherein one of X and Z is N and the other is—CH═ of structural formula I(c):

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim12 wherein X is N, Z is —CH═ and V and W are both —CH═.
 14. The compoundof claim 13, or a pharmaceutically acceptable salt thereof selected fromthose depicted in the following Table


15. The compound of claim 12 wherein X is —CH═, Z is N and V and W areboth —CH═.
 16. The compound of claim 15 or a pharmaceutically acceptablesalt thereof, selected from those depicted in the following Table;


17. The compound of claim 1 wherein R² is —COR6 of structural formulaI(d):

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim17 or a pharmaceutically acceptable salt thereof selected from thosedepicted in the following Table:


19. The compound of claim 1 of structural formula I(e), wherein one of Vor W is nitrogen and the other is —CH═.


20. The compound of claim 19 wherein R¹ and R³ ar both hydrogen.
 21. Thecompound of claim 20 wherein R² is —SO₂CH₃ or —SO₂NH₂.
 22. The compoundof claim 21 selected from the compounds depicted in the following TABLE


23. A method of treating Y5 receptor mediated diseases which comprisesadministering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of claim 1 thatselectively antagonizes the Y5 receptor in preference to the other NPYreceptors.
 24. The method of claim 23 wherein the Y5 mediated disease isobesity.
 25. A pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of aselective Y5 antagonist.